Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

• the present invention relates to a process for producing a 3-aminomethyltetrahydrofuran derivative. More specifically, the invention relates to a process for producing a 3-aminomethyltetrahydrofuran derivative reducing a 3-cyanotetrahydrofuran derivative.
• the 3-aminomethyltetrahydrofuran derivative is useful as an intermediate for medicines, agrochemicals, etc.
• a (tetrahydro-3-furanyl)methylamine derivative having a structure represented by the following formula (1) exhibits an extremely high insecticidal activity, and further has low toxicity and an extremely excellent performance as an active ingredient of agrochemicals (see Patent Document 1).
• a process for producing a 3-aminomethyltetrahydrofuran derivative as raw materials thereof is little known and only the following two methods are known. This is on the ground that the synthesis of a tetrahydrofuran compound having a substituent at the 3-position is extremely difficult, while a tetrahydrofuran compound having a substituent at the 2-position can be easily derived from the substitution reaction on the furan ring.
• R 10 , R 11 and R 12 represent a hydrogen atom or a lower alkyl group.
• a method which includes carrying out a reductive amination using tetrahydrofuran-3-carboxyaldehyde as a raw material in an aqueous ammonia solution in the presence of hydrogen is known (see Patent Document 2).
• this method cannot be said to be an industrially sufficiently advantageous method in that extremely expensive raw materials has to be used, for example, expensive 2-butene-1, 4-diol has to be subjected to cyclization and then further hydroformylation using an expensive rhodium catalyst in order to obtain tetrahydrofuran-3-carboxyaldehyde being the raw material.
• Patent Document 1 discloses a method in which 3-(tetrahydrofuryl)methylhalide or 3-(tetrahydrofuryl)methylsulfonate is derived from 3-hydroxymethyltetrahydrofuran as raw materials and is reacted with potassium phthalimide to carry out hydrolysis or hydrazinolysis.
• this method is also not industrially advantageous in that 2-hydroxymethyl-1,4-butanediol being raw materials of 3-hydroxymethyltetrahydrofuran is expensive, by-products derived from phthalimide are formed in large quantities and the highly hazardous hydrazine is used.
• a hydrogenation method of a 3-cyanotetrahydrofuran derivative there are not many synthesis examples of effectively obtaining a 3-cyanotetrahydrofuran derivative and thus examples of a process for producing a 3-aminomethyltetrahydrofuran derivative using it as raw materials are not known.
• a method of obtaining amines by reducing a cyano group is generally known, but the preferred method thereof is largely varied depending on a substrate.
• a 3-cyanotetrahydrofuran derivative and a 2-cyanotetrahydrofuran derivative as its isomer are not completely known and thus the preferred method thereof is also not completely known.
• a process for producing a 3-cyanotetrahydrofuran derivative from a 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative, which is a process according to the present invention, is not known.
• An object of the present invention is to provide a process for producing a 3-aminomethyltetrahydrofuran derivative with high efficiency from inexpensive industrial materials.
• the present inventors have intensively investigated in order to achieve the above object, and as a result, they have found a process for producing a 3-aminomethyltetrahydrofuran derivative by reducing the cyano group of a 3-cyanotetrahydrofuran derivative and further a process for producing a 3-cyanotetrahydrofuran derivative in a high yield from an inexpensive and industrially easily available malic acid derivative, and thus have completed the present invention.
• a first aspect of the present invention provides a process for producing a 3-aminomethyltetrahydrofuran derivative represented by the formula (2):
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms, which includes reducing the cyano group of a 3-cyanotetrahydrofuran derivative represented by the formula (1):
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms.
• a second aspect of the present invention provides a process for producing a 3-cyanotetrahydrofuran derivative represented by the formula (1), which includes reacting a 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative represented by the formula (3):
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms; and X represents a halogen atom or an alkylsulfonate group having 1 to 6 carbon atoms or arylsulfonate group having 6 to 12 carbon atoms, and an organic or inorganic cyano compound.
• a third aspect of the present invention provides a process for producing a 3-aminomethyltetrahydrofuran derivative by the process according to the first aspect of the present invention, which includes using the 3-cyanotetrahydrofuran derivative obtained by the process according to the second aspect of the present invention.
• a fourth aspect of the present invention provides a process for producing a 3-aminomethyltetrahydrofuran derivative by the process according to the third aspect of the present invention, which includes using a 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative represented by the formula (3a):
• the 3-aminomethyltetrahydrofuran derivative can be industrially advantageously produced from inexpensive raw materials compared to conventional processes.
• the 3-cyanotetrahydrofuran derivative according to the process of the invention is represented by the formula (1).
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms. More specific examples of the hydrocarbon group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a 2-butyl group, an isobutyl group and t-butyl group.
• 3-cyanotetrahydrofuran derivative examples include 3-cyanotetrahydrofuran substituted with a hydrocarbon group, such as 4-ethyl-3-cyanotetrahydrofuran and 3-methyl-3-cyanotetrahydrofuran, including 3-cyanotetrahydrofuran.
• the process for producing a 3-cyanotetrahydrofuran derivative used in the present invention is not limited, but the 3-cyanotetrahydrofuran derivative can be more suitably produced by a process of cyanation of a 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative.
• the 3-aminomethyltetrahydrofuran derivative represented by the formula (2) is produced by reducing the cyano group of the 3-cyanotetrahydrofuran derivative represented by the formula (1).
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are as defined for R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 in the formula (1).
• Specific examples of the 3-aminomethyltetrahydrofuran derivative include a 3-cyanotetrahydrofuran substituted with a hydrocarbon group, such as 4-ethyl-3-aminomethyltetrahydrofuran and 3-methyl-3-aminomethyltetrahydrofuran, including 3-aminomethyltetrahydrofuran.
• 3-aminomethyltetrahydrofuran is obtained when 3-cyanotetrahydrofuran is used and 3-methyl-3-aminomethyltetrahydrofuran is obtained when 3-methyl-3-cyanotetrahydrofuran is used.
• Examples of the method of reducing the cyano group of the 3-cyanotetrahydrofuran derivative in the present invention include a method of reducing with a metal hydride and a method of reducing with hydrogen in the presence of a hydrogenation catalyst.
• the specific examples of the metal hydride when reducing with the metal hydride include an aluminum hydride compound such as lithium aluminum hydride, lithium trimethoxyaluminum hydride, aluminum hydride and diisobutylaluminum hydride, and a boron hydride compound such as diborane, lithium borohydride and sodium borohydride.
• the amount used of the metal hydride when reducing by the metal hydride is usually in the range of 2 to 10 moles, preferably 3 to 6 moles per mole of a 3-cyanotetrahydrofuran derivative.
• the hydrogenation catalyst when reducing with hydrogen in the presence of the hydrogenation catalyst may be any compound as long as it catalyzes the reaction in which the cyano group of the 3-cyanotetrahydrofuran derivative according to the present invention is reduced to an aminomethyl group by a molecular hydrogen, but usually at least one metal selected from Groups 7 to 13 of the Periodic Table of the Elements or a metal compound thereof is suitably used. More specifically, it includes a metal such as manganese, rhenium, iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, gold, zinc and aluminum or metal compounds thereof.
• These metal or metal compounds may be or may not be dissolved in a reaction liquid.
• these hydrogenation catalysts include an elemental metal such as rhodium metal powders and palladium metal powders, a Raney metal compound such as Raney nickel, Raney copper and Raney cobalt, a stabilized metal compound such as stabilized nickel, a metal-supported catalyst in which a metal such as rhenium, ruthenium, rhodium, palladium is supported on the inorganic support such as carbon black, activated carbon, alumina, silica gel, diatom earth, zeolite and magnesia, a metal oxide such as ruthenium oxide, palladium oxide, rhenium oxide and copper oxide, a complex metal-oxide such as copper oxide-chromium oxide, copper oxide-zinc oxide-aluminum oxide, complex compounds of metals of Groups 8 to 10 of the Periodic Table of the Elements, such as RuClH(CO) (PPh 3 ) 3 , RuCl 2
• the amount of the hydrogenation catalyst to be used is in the range of usually 0.1 ppm by weight to 10% by weight, preferably 1 ppm by weight to 5% by weight relative to the 3-cyanotetrahydrofuran derivative when the catalyst used is dissolved in the reaction liquid, and is in the range of usually 0.1% by weight to 500% by weight, preferably 1% by weight to 200% by weight relative to the 3-cyanotetrahydrofuran derivative when the catalyst used is not dissolved in the reaction liquid.
• the hydrogenation catalyst is preferably a metal of Group 9 or 10 of the Periodic Table of the Elements or a metal compound thereof, more preferably a metal such as cobalt or nickel or a metal compound thereof, and most preferably a metal such as cobalt or a metal compound thereof.
• the method of reducing the 3-cyanotetrahydrofuran derivative of the present invention may be carried out without a solvent, but is usually carried out in the presence of the solvent.
• the suitable solvent to be used varies depending on the method of reducing the cyano group.
• aliphatic or alicyclic hydrocarbons having 5 to 20 carbon atoms such as n-hexane, n-pentane or cyclohexane
• aromatic hydrocarbons having 6 to 20 carbon atoms such as benzene, toluene and ethylbenzene
• aliphatic or aromatic halides having 1 to 20 carbon atoms such as chloroform, chlorobenzene and dichlorobenzene
• ethers having 2 to 20 carbon atoms such as diethyl ether, diphenyl ether, tetrahydrofuran and ethylene glycol dimethyl ether
• these solvents may be used in a mixture of two or more thereof. Of these solvents, ethers are particularly used.
• the solvent to be used when reducing with hydrogen in the presence of hydrogenation catalyst for example, water, alcohols having 1 to 20 carbon atoms, such as methanol, ethanol, butanol, aliphatic or alicyclic hydrocarbons having 5 to 20 carbon atoms, such as n-hexane, n-pentane or cyclohexane, benzene, aromatic hydrocarbons having 6 to 20 carbon atoms, such as toluene and ethylbenzene, and ethers having 2 to 20 carbon atoms, such as diethyl ether, diphenyl ether, tetrahydrofuran and ethylene glycol dimethyl ether, are suitably used. Further, these solvents may be used in a mixture of two or more thereof. Of these solvents, water, alcohols and ethers are preferably used, and water is more preferably used.
• the amount of the solvent used is not uniform over reaction conditions, but is in the range of usually 0.01 to 200 parts by weight, preferably 0.02 to 50 parts by weight, more preferably 0.05 to 2 parts by weight per part by weight of the 3-cyanotetrahydrofuran derivative.
• ammonia refers to aqueous ammonia, liquid ammonia or ammonia gas, but ammonia is more preferably aqueous ammonia.
• the amount of ammonia used is not particularly limited, but is in the range of usually 0.01 to 50 mols, preferably 0.1 to 20 mols, more preferably 0.3 to 5 moles relative to 1 mole of the 3-cyanotetrahydrofuran derivative.
• the method of reducing the 3-cyanotetrahydrofuran derivative of the present invention is particularly preferably a method of reducing with hydrogen in the presence of ammonia and also in the presence of a metal of Group 9 or 10 of the Periodic Table of the Elements or a metal compound thereof, as a catalyst.
• the catalyst is more preferably a metal of nickel or cobalt or a metal compound thereof and ammonia is more preferably aqueous ammonia.
• the reaction is carried out in the presence of aqueous ammonia, it is preferably carried out in the presence of 0.05 to 2 parts by weight of aqueous ammonia relative to 1 part by weight of the 3-cyanotetrahydrofuran derivative.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are preferably a hydrogen atom.
• the temperature and time in the reaction are not uniform over the kinds of the 3-cyanotetrahydrofuran derivative and the reduction method.
• the reaction temperature is in the range of usually -10 to 150°C, preferably 0 to 120°C, more preferably 10 to 100°C.
• the reaction temperature is in the range of usually 0 to 250°C, preferably 50 to 200°C, more preferably 80 to 150°C.
• the reaction time is in the range of usually not more than 100 hours, preferably 0.01 to 50 hours.
• the pressure in the reaction may be any of reduced pressure, normal pressure or pressurization, but the preferable mode varies depending on the reduction method to be performed.
• reducing with the metal hydride it is preferably carried out at normal pressure.
• reducing with hydrogen in the presence of the hydrogenation catalyst it is preferably carried out under hydrogen pressurization.
• the hydrogen pressure in pressurization is in the range of usually 0.01 to 25 MPaG, preferably 0.1 to 20 MPaG, more preferably 1 to 10 MPaG.
• the reaction process of reducing the cyano group is not particularly limited and may be performed in any one of batch, semibatch and continuous flow modes.
• the catalyst used may be recovered by the conventional process for recovery of metals after completion of the reaction.
• the catalyst when the catalyst is dissolved in the reaction liquid, the catalyst can be recovered by contacting with a metal adsorbent such as an ion-exchange resin or by extracting with the solvent.
• the catalyst when the catalyst is not dissolved in the reaction liquid, the catalyst can be recovered by a solid-liquid separation method such as filtration and centrifugal separation.
• These recovered catalysts can be repeatedly used as the hydrogenation catalyst. In that case, it may be reused after the catalyst deactivated or having reduced activity is subjected to a recycling operation or may be used by adding the fresh catalyst.
• the 3-aminomethyltetrahydrofuran derivative formed by the method of reducing the 3-cyanotetrahydrofuran derivative of the present invention can be isolated according to the conventional separation method such as distillation.
• the 3-cyanotetrahydro furan derivative represented by the formula (1) is prepared by reacting the 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative represented by the formula (3) and an organic or inorganic cyano compound.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are as defined for R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 in the formula (1) ; and X represents a halogen atom or an alkylsulfonate group having 1 to 6 carbon atoms or an arylsulfonate group having 6 to 12 carbon atoms.
• halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom
• alkylsulfonate group having 1 to 6 carbon atoms include a hydrocarbon alkylsulfonate group having 1 to 6 carbon atoms such as a methylsulfonate group, an ethylsulfonate group, and a halogen group-substituted alkylsulfonate group having 1 to 6 carbon atoms such as a trifluoromethylsulfonate group and a 1,1,1-trifluoroethylsulfonate group.
• examples of the arylsulfonate group having 6 to 12 carbon atoms include a hydrocarbon arylsulfonate group having 6 to 12 carbon atoms such as a benzenesulfonate group and a p-toluenesulfonate group and a halogen group-substituted arylsulfonate group having 6 to 12 carbon atoms such as a p-trifluoromethyl benzenesulfonate group.
• 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative include 3-halogenated tetrahydrofuran such as 3-chlorotetrahydrofuran and 3-bromotetrahydrofuran, a hydrocarbon group-substituted 3-halogenated tetrahydrofuran such as 4-ethyl-3-chlorotetrahydrofuran and 3-methyl-3-iodotetrahydrofuran, 3-alkyl or arylsulfonated tetrahydrofuran such as 3-(p-toluenesulfonato)-tetrahydrofuran, 3-trifluoromethanesulfonatotetrahydrofuran and a hydrocarbon group-substituted 3-alkyl or arylsulfonated tetrahydrofuran such as 4-ethyl-3-benzenesulfonatotetra
• the process for producing the 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative used in the process of the present invention is not limited, but it can be suitably produced by using a malic acid derivative described below as a starting material.
• the organic or inorganic cyano compound used in the process of the present invention is an organic or inorganic cyano compound capable of converting a halogen group or alkyl or arylsulfonate group at the 3-position of the 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative to the cyano group.
• Specific examples of the organic cyano compound include a hydrogen cyanide adduct of ketone or aldehyde having 1 to 20 carbon atoms, such as glycolonitrile and acetonecyanhydrin and a cyanated organic ammonium salt such as tetramethylammonium cyanide and triethylammonium cyanide.
• the inorganic cyano compound examples include ammonium cyanide, an alkali metal cyanide such as lithium cyanide, sodium cyanide and potassium cyanide, an alkaline earth metal cyanide such as magnesium cyanide, a transition metal cyanide of Groups 3 to 12 of the Periodic Table of the Elements, such as manganese cyanide, copper cyanide and cyanide ruthenium, including hydrogen cyanide.
• an alkali metal cyanide such as lithium cyanide, sodium cyanide and potassium cyanide
• an alkaline earth metal cyanide such as magnesium cyanide
• a transition metal cyanide of Groups 3 to 12 of the Periodic Table of the Elements such as manganese cyanide, copper cyanide and cyanide ruthenium, including hydrogen cyanide.
• the hydrogen cyanide adduct of ketone or aldehyde having 1 to 20 carbon atoms and the alkali metal cyanide are preferred and the alkali metal cyanide is
• the amount of the organic or inorganic cyano compound used is in the range of usually 0.1 to 10 moles, preferably 0.8 to 3 moles per mole of the 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative.
• a compound accelerating a cyanation can be added to the reaction mixture.
• the compound accelerating a cyanation include a halogenated ammonium salt such as tetraethylammonium chloride, tetraethylammonium bromide, triethylammonium chloride and cetylpyridinium chloride, a halogenated phosphonium salt such as tetraphenylphosphonium chloride and tetraphenylphosphonium bromide, a cyclic ether compound such as 15-crown -5-ether and 18-crown -6-ether, a halogenated phosphazenium salt such as phosphazenium chloride, a halogenated alkali metal or alkaline earth metal such as sodium chloride, lithium chloride, potassium bromide, magnesium chloride, sodium iodide and potassium iodide, and
• the method of cyanation of the compound represented by the formula (3) of the present invention may be carried out in the absence of a solvent, but is usually carried out in the presence of a solvent.
• the solvent used include monohydric or polyhydric alcohols having 1 to 20 carbon atoms such as methanol, ethanol, butanol and ethylene glycol, aliphatic or alicyclic hydrocarbons having 5 to 20 carbon atoms such as n-hexane, n-pentane and cyclohexane, aromatic hydrocarbons having 6 to 20 carbon atoms such as benzene, toluene and ethylbenzene, aliphatic or aromatic halides having 1 to 20 carbon atoms such as chloroform, chlorobenzene and dichlorobenzene, ethers having 2 to 20 carbon atoms such as diethyl ether, diphenyl ether, tetrahydrofuran and ethylene glycol dimethyl ether, aliphatic or aromatic amide
• the solvent having permittivity of 20 F ⁇ m -1 or more it is preferable to use the solvent having permittivity of 20 F ⁇ m -1 or more.
• the term "permittivity" as used in the present invention refers to permittivity at 20 to 30°C.
• the preferable solvent of the present invention does not have permittivity of 20 F ⁇ m -1 or more over the total temperature range, and includes any solvent as long as it has permittivity of 20 F ⁇ m -1 or more over a part of the temperature range.
• the permittivity of the solvent can take values described in " Solvent Handbook" (Shozo Asahara, et al., published by Kodansha Ltd.
• the solvent having the permittivity of 20 F ⁇ m -1 or more include methanol, ethanol, propanol, ethylene glycol, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide and N-methylpyrrolidone, but is not limited thereto.
• solvents having the permittivity of 20 F ⁇ m -1 or more solvent it is more preferable to use an aprotic solvent. Further, of these solvents, it is most preferable to use aliphatic or aromatic amides, aliphatic or aromatic imidazolidinones, or aliphatic or aromatic sulfoxides, each of which has the permittivity of 20 F ⁇ m -1 or more.
• solvents may be used in a mixture of two or more thereof.
• the amount thereof is not uniform over reaction conditions, but is in the range of usually 0.1 to 500 parts by weight, preferably 1 to 200 parts by weight, more preferably 2 to 100 parts by weight relative to 1 part by weight of the 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative.
• the alkali metal cyanide as the cyano compound and react it in the presence of the solvent having the permittivity of 20 F ⁇ m -1 or more.
• the solvent having the permittivity of 20 F ⁇ m -1 or more is more preferably the aprotic solvent.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are preferably a hydrogen atom.
• X is preferably a halogen atom, more preferably a chlorine atom.
• the reaction temperature is in the range of usually 0°C to 250°C, preferably 20 to 200°C, more preferably 50 to 180°C.
• the reaction time is in the range of usually not more than 100 hours, preferably 0.01 to 50 hours.
• the pressure in the reaction may be any of reduced pressure, normal pressure or pressurization.
• the reaction process of the present invention is not particularly limited and may be performed in any one of batch, semibatch and continuous flow modes.
• the compound accelerating the reaction when used may be also recovered and repeatedly used in the following reaction.
• the 3-cyanotetrahydrofuran derivative formed in the process of the present invention can be isolated according to the conventional separation method such as distillation and extraction.
• the 3-cyanotetrahydrofuran derivative and subsequently produce the 3-aminomethyltetrahydrofuran derivative by using the 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative represented by the formula (3a), which is prepared from the malic acid derivative by the following first to third steps, according to the process of the present invention.
• R 1 , R 2 , R 3 , R 8 and R 9 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms, are reduced to prepare triols represented by the formula (5):
• R 1 , R 2 and R 3 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms, corresponding to the malic acid derivative used.
• the triols represented by the formula (5) obtained from the first step is subjected to an intramolecular dehydration reaction in the presence of an acid catalyst to prepare a 3-hydroxytetrahydrofuran derivative represented by the formula (6):
• R 1 , R 2 and R 3 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms, corresponding to the triols used.
• the 3-hydroxytetrahydrofuran derivative represented by the formula (6) obtained from the second step and a halogenating agent or alkyl or arylsulfonylating agent are reacted to halogenate or alkyl or arylsulfonate a hydroxyl group thus to prepare the 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative represented by the formula (3a):
• R 1 , R 2 and R 3 may be the same or different from each other and each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms; and X represents a halogen atom, or an alkylsulfonate group having 1 to 6 carbon atoms or an arylsulfonate group having 6 to 12 carbon atoms.
• the malic acid derivative represented by the formula (4) is used as raw materials.
• R 1 , R 2 and R 3 are as defined for R 1 , R 2 and R 3 in the formula (1);
• R 8 and R 9 each represent a hydrogen atom or a hydrocarbon group having 1 to 4 carbon atoms.
• the malic acid derivative include malic acid substituted by a hydrocarbon group at the 2-positon and/or 3-position, such as citramalic acid (2-methylmalic acid), 3-ethylmalic acid and 3, 3-dimethylmalic acid, malic monoester or diester such as monoisopropyl malate, dimethyl malate and diethyl malate, and monoester or diester substituted by a hydrocarbon group at the 2-positon and/or 3-position, such as dimethyl citramalate, monobutyl citramalate and dimethyl 3-ethylmalate, including malic acid.
• malic acid derivatives have an asymmetric carbon, but the malic acid derivative used in the present invention may be an optically active substance or racemate.
• malic acid derivatives it is preferable to use malic acid, or malic monoester or diester, more preferably malic acid.
• the -COOR 8 group and -COOR 9 group of the malic acid derivative represented by the formula (4) are reduced to prepare the triols represented by the formula (5):
• R 1 , R 2 and R 3 are as defined for R 1 , R 2 and R 3 in the formula (1).
• More specific examples of the triols include 1,2,4-butanetriol substituted by a hydrocarbon group at the 2-positon and/or 3-position, such as 2-methyl-1,2,4-butanetriol and 3-butyl-1,2,4-butanetriol, including 1,2,4-butanetriol.
• the triols obtained in the first step of the present invention corresponds to the malic acid derivative and a hydrogen atom or hydrocarbon group at the 2-position and the 3-position of the malic acid derivative used is the same as a hydrogen atom or hydrocarbon group of the 2-position and the 3-position of the triols obtained.
• citramalic acid (2-methylmalic acid) and dimethyl 3-ethylmalate are used as the malic acid derivative, respectively.
• 1,2,4-butanetriol, 2-methyl-1,2,4-butanetriol and 3-ethyl-1,2,4-butanetriol are obtained, respectively.
• examples of the method of reducing the -COOR 8 group and -COOR 9 group of the malic acid derivative represented by the formula (4) include a method of electrolytic reduction, a method of reducing with the metal hydride, a method of reducing with hydrogen in the presence of the hydrogenation catalyst.
• Specific examples of the method of electrolytic reduction include a method of electrolytic reduction using a lead electrode in an aqueous sulfuric acid solution.
• the metal hydride When reducing with the metal hydride, specific examples of the metal hydride include the aluminum hydride compound such as lithium aluminum hydride, lithium trimethoxyaluminum hydride, aluminum hydride and diisobutylaluminum hydride and the boron hydride compound such as diborane, lithium borohydride and sodium borohydride.
• the amount of the metal hydride when reducing with the metal hydride is in the range of usually 2 to 10 moles, preferably 3 to 6 moles per mole of the malic acid derivative.
• the hydrogenation catalyst when reducing with hydrogen in the presence of the hydrogenation catalyst may be also any compound as long as it catalyzes the reaction in which the carboxyl group or ester group of the malic acid derivative according to the present invention is reduced to a hydroxyl group by a molecular hydrogen, but usually at least one metal selected from Groups 7 to 13 of the Periodic Table of the Elements or a metal compound thereof is suitably used.
• Specific examples of the hydrogenation catalyst and the amount used thereof may be exemplified by the same as those exemplified in the method of reducing the cyano groups of the 3-cyanotetrahydrofuran derivative represented by the formula (1).
• the hydrogenation catalyst is preferably a metal such as ruthenium, rhodium, palladium, copper or rhenium or a metal compound thereof, more preferably a metal such as ruthenium or rhodium or metal compound thereof, and most preferably a metal such as ruthenium or metal compound thereof.
• the first step of the preferable process of the present invention may be carried out without a solvent, but is usually carried out in the presence of the solvent.
• the solvent may be any solvent as long as it does not inhibit the reduction reaction.
• solvent used in the method of electrolytic reduction water and alcohols having 1 to 20 carbon atoms, methanol, ethanol and butanol, are suitably used. Further, these solvents may be used in a mixture of two or more thereof.
• aliphatic or alicyclic hydrocarbons having 5 to 20 carbon atoms such as n-hexane, n-pentane and cyclohexane
• aromatic hydrocarbons having 6 to 20 carbon atoms such as benzene, toluene and ethylbenzene
• aliphatic or aromatic halide havings 1 to 20 carbon atoms such as chloroform, chlorobenzene and dichlorobenzene
• ethers having 2 to 20 carbon atoms such as diethyl ether, diphenyl ether, tetrahydrofuran and ethylene glycol dimethyl ether
• these solvents may be used in a mixture of two or more thereof. Of these solvents, it is preferable to use ethers.
• water As the solvent used when reducing with hydrogen in the presence of the hydrogenation catalyst solvent, water, alcohols having 1 to 20 carbon atoms such as methanol, ethanol and butanol, aliphatic or alicyclic hydrocarbons having 5 to 20 carbon atoms such as n-hexane, n-pentane and cyclohexane, aromatic hydrocarbons having 6 to 20 carbon atoms such as benzene, toluene and ethylbenzene and ethers having 2 to 20 carbon atoms such as diethyl ether, diphenyl ether, tetrahydrofuran and ethylene glycol dimethyl ether are suitably used. Further, these solvents may be used in a mixture of two or more thereof. Of these solvents, it is preferable to use water, alcohols and ethers, more preferably water or alcohols having 1 to 4 carbon atoms.
• the amount thereof is not uniform over reaction conditions, but is in the range of usually 0.1 to 500 parts by weight, preferably 1 to 200 parts by weight relative to 1 part by weight of the malic acid derivative.
• the temperature and time in the reaction are not uniform over the kinds of the malic acid derivative used and the reduction method.
• the reaction temperature is in the range of usually -10 to 250°C, preferably 10 to 200°C.
• the reaction time is in the range of usually not more than 150 hours, preferably 0.01 to 100 hours.
• the pressure in the reaction may be any of reduced pressure, normal pressure or pressurization, but the preferable mode varies depending on the reduction method to be performed.
• reducing with the metal hydride it is preferably carried out at normal pressure.
• electrolytic reduction or reducing with the metal hydride it is preferably carried out at normal pressure.
• reducing with hydrogen in the presence of the hydrogenation catalyst it is preferably carried out under hydrogen pressurization.
• the hydrogen pressure in pressurization is in the range of usually 0.01 to 30 MPaG, preferably 0.1 to 25 MPaG.
• reaction process of the first step of the preferable process of the present invention is not particularly limited and may be performed in any one of batch, semibatch and continuous flow modes.
• the catalyst used may be recovered by the conventional process for recovery of metals after completion of the reaction.
• the catalyst when the catalyst is dissolved in the reaction liquid, the catalyst can be recovered by contacting with a metal adsorbent such as an ion-exchange resin or by extracting from the solvent.
• the catalyst when the catalyst is not dissolved in the reaction liquid, the catalyst can be recovered by a solid-liquid separation method such as filtration and centrifugal separation.
• These recovered catalysts can be repeatedly used as the hydrogenation catalyst of the first step of the present invention. In that case, it may be also reused after the catalyst deactivated or having reduced activity is subjected to a recycling operation.
• the reaction liquid itself may be provided in the following step without recovering the catalyst as long as the remaining catalyst does not affect the subsequent recovery step of the triols and/or the second step of the preferable process of the present invention.
• the triols formed in the first step of the preferable process of the present invention may be provided in the following second step after isolation according to the conventional separation method such as distillation, may be provided in the following step as a mixture after distilling off only the solvent when the solvent is used, or may be provided in the following step as the reaction mixture itself, which contains the solvent.
• the triols obtained from the first step is subjected to an intramolecular dehydration reaction in the presence of an acid catalyst to prepare the 3-hydroxytetrahydrofuran derivative represented by the formula (6):
• R 1 , R 2 and R 3 are as defined for R 1 , R 2 and R 3 in the formula (1).
• the 3-hydroxytetrahydrofuran derivative include a 3-hydroxytetrahydrofuran substituted by a hydrocarbon group at the 3-positon and/or 4-position, such as 4-ethyl-3-hydroxytetrahydrofuran and 3-methyl-3-hydroxytetrahydrofuran, including 3-hydroxytetrahydrofuran.
• the 3-hydroxytetrahydrofuran derivative obtained in the second step corresponds to the triols used and a hydrogen atom or hydrocarbon group at the 2-position and the 3-position of the triols used is the same as a hydrogen atom or hydrocarbon group of the 3-position and the 4-position of the 3-hydroxytetrahydrofuran derivative obtained.
• a hydrogen atom or hydrocarbon group at the 2-position and the 3-position of the triols used is the same as a hydrogen atom or hydrocarbon group of the 3-position and the 4-position of the 3-hydroxytetrahydrofuran derivative obtained.
• the acid catalyst in the second step of the preferable process of the present invention may be any one of Bronsted acid and Lewis acid and may be soluble or insoluble in the reaction mixture.
• the acid catalyst may be any one of an organic acid, an inorganic acid and a solid acid and specific examples thereof include inorganic acids such as hydrochloric acid , hydrobromic acid, boric acid , nitric acid , sulfuric acid, phosphoric acid and chloric acid, organic carboxylic acids such as formic acid, acetic acid, propionic acid, chloroacetic acid, glycolic acid, benzoic acid and phthalic acid, organic sulfonic acids such as methylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid, organic phosphoric acids such as diethyl phosphate and phenyl phosphate, metal halides such as aluminum chloride, zinc iodide and titanium chloride, metal salts
• the amount of the acid catalyst used is in the range of usually 0.0001 to 10 mol%, preferably 0.001 to 5 mol% when soluble in the triols as raw materials of the second step and is in the range of usually 0.001 to 50% by weight, preferably 0.1 to 20% by weight when insoluble in the triols.
• the second step of the preferable process of the present invention can be carried out in the presence of the solvent.
• the solvent may be any solvent as long as it does not inhibit the intramolecular dehydration reaction of the triols.
• the solvent among the solvents exemplified as those usable in the first step, aliphatic or alicyclic hydrocarbons having 5 to 20 carbon atoms, aromatic hydrocarbons having 6 to 20 carbon atoms, aliphatic or aromatic halides having 1 to 20 carbon atoms and ethers having 2 to 20 carbon atoms, are suitably used. Further, these solvents may be used in a mixture of two or more thereof.
• the amount of the solvent used is not uniform over reaction conditions, but is in the range of usually 0.1 to 500 parts by weight, preferably 1 to 200 parts by weight per part by weight of the triols.
• the second step of the preferable process of the present invention is preferably carried out while water formed by the intramolecular dehydration reaction is removed out of the reaction system.
• a method of removing the water formed out of the reaction system is not particularly limited, but examples thereof include a method of distilling off water formed by carrying out the reaction under reduced pressure out of the reaction system, a method of removing an azeotropic mixture obtained by carrying out the reaction in the presence of the solvent such as toluene which is azeotropic with water, out of the reaction system and a method of coexisting a dehydrating agent in the reaction liquid.
• the reaction temperature in the second step of the preferable process of the present invention is in the range of usually 10 to 250°C, preferably 30 to 200°C.
• the reaction time is in the range of usually not more than 100 hours, preferably 0.01 to 50 hours.
• the pressure in the reaction may be any of reduced pressure, normal pressure or pressurization, but the preferable mode varies depending on the reduction method to be performed.
• the reaction is preferably carried out under reduced pressure when it is carried out while distilling off the water formed.
• the reaction process of the present invention is not particularly limited and may be performed in any one of batch, semibatch and continuous flow modes.
• the catalyst used may be also recovered and repeatedly used in the following reaction.
• the catalyst may be neutralized with a base such as sodium hydroxide.
• the catalyst may be separated by a conventional solid-liquid separation or the catalyst itself may be used in the following purification step without neutralization or separation.
• the 3-hydroxytetrahydrofuran derivative formed in the second step of the preferable process of the present invention may be provided in the following third step after isolation according to a conventional separation such as distillation or may be further provided in the following step as the reaction mixture.
• the 3-hydroxytetrahydrofuran derivative obtained from the second step and a halogenating agent or alkyl or arylsulfonylating agent are reacted to halogenate or alkyl or arylsulfonate a hydroxyl group thus to prepare the 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative represented by the formula (3a):
• R 1 , R 2 , R 3 and X are as defined for R 1 , R 2 , R 3 and X in the formula (3).
• the 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative represented by the formula (3a) is a compound wherein all of R 4 , R 5 , R 6 and R 7 are a hydrogen atom, among the compounds represented by the formula (3).
• the 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative obtained in the third step of the preferable process of the present invention corresponds to the 3-hydroxytetrahydrofuran derivative used and a hydrogen atom or hydrocarbon group at the 3-position and the 4-position of the 3-hydroxytetrahydrofuran derivative used is the same as a hydrogen atom or hydrocarbon group of the 3-position and the 4-position of the 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative obtained.
• 3-hydroxytetrahydrofuran and 3-methyl-3-hydroxytetrahydrofuran are used as the 3-hydroxytetrahydrofuran derivative, respectively.
• 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran and 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated-3-methyltetrahydrofuran are obtained, respectively.
• the halogenating agent in the third step of the preferable process of the present invention may be any compound as long as the hydroxyl group of the 3-hydroxytetrahydrofuran derivative can be efficiently converted to a halogen group and examples of the halogenating agent include the halogenating agent used in the synthesis of a halogen compound from an alcohol compound, which is described in Experimental Chemistry Course, Vol. 20 (edited by The Chemical Society of Japan, published by Maruzen Co., Ltd. (1956 )) or New Experimental Chemistry Course, Vol. 14 (I) (edited by The Chemical Society of Japan, published by Maruzen Co., Ltd. (1977 )).
• halogenating agent examples include a fluorinating agent such as an EiF/pyridine solution, 1,1,2,2-tetrafluoroethyldiethylamine and trifluorodiphenylphosphorane, a chlorinating agent such as phosgene, thionyl chloride, zinc chloride/hydrochloric acid , t-butyl hypochlorite and N-chlorinated amine, a brominating agent such as hydrobromic acid, t-butyl hypobromite and thionyl bromide and an iodinating agent such as hydriodic acid.
• a fluorinating agent such as an EiF/pyridine solution, 1,1,2,2-tetrafluoroethyldiethylamine and trifluorodiphenylphosphorane
• a chlorinating agent such as phosgene, thionyl chloride, zinc chloride/hydrochloric acid , t-butyl hypochlorit
• chlorinating agents it is preferable to use phosgene or thionyl chloride.
• the amount of the halogenating agent used is in the range of usually 0.1 to 10 moles, preferably 0.8 to 3 moles per mole of the 3-hydroxytetrahydrofuran derivative.
• the alkyl or arylsulfonylating agent in the third step of the preferable process of the present invention may be any compound as long as it can efficiently convert the hydroxyl group of the 3-hydroxytetrahydrofuran derivative into an alkyl or arylsulfonate group.
• alkyl or arylsulfonylating agent examples include alkylsulfonic acids having 1 to 6 carbon atoms or arylsulfonic acids having 6 to 12 carbon atoms, such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid and trifluoromethanesulfonic acid, halides of the alkyl or arylsulfonic acids, such as tosyl chloride (p-toluenesulfonic acid chloride), ammonium salts of the alkyl or arylsulfonic acids such as ammonium trifluoromethanesulfonate and tetraethylammonium benzenesulfonate, alkali metal salts of the alkyl or arylsulfonic acids such as sodium p-toluenesulfonate, anhydrides of the alkylsul
• alkyl or arylsulfonylating agents it is preferable to use halides and anhydrides of the alkyl or arylsulfonic acids, more preferably halides of the alkyl or arylsulfonic acids.
• the amount of the alkyl or arylsulfonylating agent used is in the range of usually 0.1 to 10 moles, preferably 0.8 to 3 moles per mole of the 3-hydroxytetrahydrofuran derivative.
• the suitable catalyst and reaction accelerator can be used in order to efficiently react the 3-hydroxytetrahydrofuran derivative and the halogenating agent or alkyl or arylsulfonylating agent.
• the catalyst and reaction accelerator when used varies depending on the halogenating agent or alkyl or arylsulfonylating agent.
• amines such as pyridine and triethylamine
• amides such as N,N-dimethylformamide and N,N-dimethylacetamide are used to accelerate the reaction and thus improve the yield.
• halides of the alkyl or arylsulfonic acids such as tosyl chloride are used, it is preferable to use amines such as pyridine and triethylamine.
• the third step of the preferable process of the present invention may be carried out in the absence or in the presence of a solvent.
• the solvent may be any solvent as long as it does not inhibit the reaction of the 3-hydroxytetrahydrofuran derivative and the halogenating agent or alkyl or arylsulfonylating agent.
• aliphatic or aromatic amides having 2 to 20 carbon atoms such as N,N-dimethylformamide and N,N-dimethylacetamide
• aliphatic or aromatic esters having 2 to 20 carbon atoms such as ethyl acetate and butyl acetate
• aliphatic or aromatic nitriles having 2 to 20 carbon atoms such as acetonitrile and benzonitrile
• aliphatic or aromatic sulfoxides having 2 to 20 carbon atoms such as dimethylsulfoxide
• aromatic hydrocarbons having 6 to 20 carbon atoms, aliphatic or aromatic halides having 1 to 20 carbon atoms and ethers having 2 to 20 carbon atoms are suitably used.
• these solvents may be used in a mixture of two or more thereof.
• the amount of the solvent used is not uniform over reaction conditions, but is in the range of usually 0.1 to 500 parts by weight, preferably 1 to 200 parts by weight per part by weight of the 3-hydroxytetrahydrofuran derivative.
• the reaction temperature is in the range of usually -80 to 150°C, preferably -20 to 80°C.
• the reaction time is in the range of usually not more than 200 hours, preferably 0.01 to 100 hours.
• the pressure in the reaction may be any of reduced pressure, normal pressure or pressurization.
• the reaction process of the present invention is not particularly limited and may be performed in any one of batch, semibatch and continuous flow modes.
• the catalyst or reaction accelerator when used may be also recovered and repeatedly used in the following reaction, and may be separated by the conventional separation method.
• the 3-halogenated or 3-alkylsulfonated or 3-arylsulfonated tetrahydrofuran derivative formed in the third step of the preferable process of the present invention may be provided in the following step after isolation according to the conventional separation method such as distillation and extraction.
• the 3-aminomethyltetrahydrofuran formed was distilled under reduced pressure to isolate as a transparent liquid being a fraction of 67°C/2.0 kPa.
• Example 1 Reaction and after-treatment were carried out in the same manner as in Example 1, except that, in Example 1 wherein an equal amount of 3-cyanotetrahydrofuran was used, the type and the amount of the catalyst, the amount of 25% aqueous ammonia, the hydrogen pressure, the reaction temperature and the reaction time were replaced as shown in Table 1. The results are shown in Table 1 together with those of Example 1.
• Reaction and after-treatment were carried out in the same manner as in Example 16, except that, in Example 16 wherein DMF was used as a solvent, the reaction temperature was adjusted to 170°C and the reaction time was adjusted to 4 hours. The conversion rate was 100% and the yield of 3-cyanotetrahydrofuran was 74.6%.
• Example 16 Reaction and after-treatment were carried out in the same manner as in Example 16, except that, in Example 16 wherein DMF was used as a solvent, the amount of the solvent was adjusted to 130 mL. The conversion rate was 100% and the yield of 3-cyanotetrahydrofuran was 87.0%.
• Example 17 Reaction and after-treatment were carried out in the same manner as in Example 17, except that, in Example 17 wherein dimethylsulfoxide (hereinafter abbreviated to "DMSO") was used as a solvent, the reaction temperature was adjusted to 120°C. The conversion rate was 98.1% and the yield of 3-cyanotetrahydrofuran was 89.3%.
• DMSO dimethylsulfoxide
• Example 17 Reaction and after-treatment were carried out in the same manner as in Example 17, except that, in Example 17 wherein DMSO was used as a solvent, the reaction temperature was adjusted to 110°C and the reaction time was adjusted to 8 hours. The conversion rate was 94.3% and the yield of 3-cyanotetrahydrofuran was 86.3%.
• Example 17 Reaction and after-treatment were carried out in the same manner as in Example 17, except that, in Example 17 wherein DMSO was used as a solvent, the amount used of NaCN was adjusted to 13.5 g (275 mmol). The conversion rate was 99.7% and the yield of 3-cyanotetrahydrofuran was 87.0%.
• Reaction and distillation were carried out in the same manner as in the first step of Example 33, except that, in the first step of Example 33, 40 g of 5% rhodium-carbon powders was used instead of 40 g of 5% ruthenium-carbon powders and hydrogen pressure was adjusted to 16 MPaG.
• the yield of 1,2,4-butanetriol was 56%.
• Reaction and distillation were carried out in the same manner as in the first step of Example 33, except that, in the first step of Example 33, 400 mL of ethanol was used instead of 400 mL of water as a solvent, hydrogen pressure was changed to 16 MPaG and the reaction time was changed to 90 hours. The yield of 1,2,4-butanetriol was 90%.
• Reaction and distillation were carried out in the same manner as in the first step of Example 33, except that, in the first step of Example 33, 400 mL of ethanol was used instead of 400 mL of water as a solvent, hydrogen pressure was changed to 16 MPaG, the reaction temperature was changed to 120°C and the reaction time was changed to 70 hours.
• the yield of 1,2,4-butanetriol was 90%.
• Reaction was carried out in the same manner as in the third step of Example 33, except that, in the third step of Example 33, 22.1 g (280 mmol) of pyridine and 50 mL of toluene were used instead of DMF. After completion of the reaction, the sulfur dioxide and hydrogen chloride formed were ejected by nitrogen bubbling, the precipitated pyridinium salt was filtered off, and then the resulting product was distilled under normal pressure to obtain 3-chlorotetrahydrofuran. The yield was 93%.

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